After the discovery of a new drug for treatment of a human disease, further investigation is undertaken to determine if the drug is most effectively administered to a patient intravenously, transdermally, subcutaneously or orally. Orally administered drugs are often favored whenever an oral route is feasible.
Pharmacokinetic studies can yield important information about how to get an optimum therapeutic response from a drug. For some drugs, maintaining a constant bloodstream and tissue concentration throughout the course of therapy is the most desirable mode of treatment. Immediate release of these drugs can cause blood levels to peak above the level required to elicit the desired response, which wastes the drug and may cause or exacerbate toxic side effects.
Many drugs provide better therapy when they are delivered in a controlled release manner. There are known dosage forms that are capable of sustaining or delaying release of a drug. In some sustained release dosage forms, the active ingredient is embedded in a matrix that slowly erodes to release the active ingredient. Other sustained and delayed release dosage forms have a coating. The coating on a sustained release dosage form may be semipermeable to the drug and thereby slow its release. The coating on some conventional delayed release dosage forms is impermeable to the drug and dissolves slowly in gastrointestinal fluid, thereby delaying release of the active ingredient until dissolution of the coating allows gastrointestinal fluid to contact the drug. However, semipermeable and impermeable coatings and conventional erodible matrices are often ineffective for sustained and delayed release of drugs with site specific absorption.
Many orally-administered drugs are most readily absorbed by the jejunum and duodenum. Other drugs are most readily absorbed through the stomach wall. Few drugs are efficiently absorbed by the colon. The residence time of a conventional dosage form in the stomach is 1 to 3 hours on average. After transiting the stomach, there is an approximately 3 to 5 hour window of bioavailability before the dosage form reaches the colon. Sustained or delayed release vehicles that are not retained in the stomach before and during release of the drug may release a significant portion of the drug after the window of bioavailability has passed. However, if the dosage form is retained in the stomach, the active ingredient will be released upstream of the small intestine and will enter the intestine in solution, a state in which it can be readily absorbed. Gastric retention dosage forms, i.e., dosage forms that are designed to be retained in the stomach for a prolonged period of time, can increase the bioavailability of drugs that are most readily absorbed by the upper gastrointestinal tract.
Another important application of gastric retention dosage forms is to improve the bioavailability of a drug that is unstable to the basic conditions of the intestine. A composition that is formulated to dissolve upon contact with any aqueous solution will at least partially dissolve in the stomach because it reaches the stomach before it reaches the intestine. However, unless the drug is very rapidly absorbed, or the residence time is increased, some of the drug will pass into the intestine. An unstable drug will at least partially decompose to a product compound that either is not absorbed or, if absorbed, may not exert the desired therapeutic effect. Accordingly, decomposition of a base sensitive drug that passes into the intestine reduces the effectiveness of the dosage and introduces an uncontrollable factor that is detrimental to accurate dosing.
Another important application of gastric retention is to deliver drugs to the active site for treatment of local disorders of the stomach, such as peptic ulcers.
For the foregoing reasons, pharmaceutical formulation specialists have developed strategies to increase the residence time of oral dosage forms in the stomach. One of the general strategies is intragastric expansion, wherein expansion of the dosage form prevents it from passing through the pylorus. The diameter of the pylorus varies between individuals from about 1 to about 4 cm, averaging about 2 cm. An expanding gastric retention dosage form must expand to at least 2 cm×2 cm in two dimensions to cause gastric retention, though a size of 2.5 cm×2 cm is more desirable.
One type of intragastric expanding dosage form uses hydrogels to expand the dosage form upon contact with gastric fluid to sufficient size to prevent its passage through the pylorus. An example of such a dosage form is described in U.S. Pat. No. 4,434,153. The '153 patent discloses a device for executing a therapeutic program after oral ingestion, the device having a matrix formed of a non-hydrated hydrogel and a plurality of tiny pills containing a drug dispersed throughout the matrix.
As noted in Hwang, S. et al. “Gastric Retentive Drug-Delivery Systems,” Critical Reviews in Therapeutic Drug Carrier Systems, 1998, 15, 243-284, one of the major problems with intragastric expanding hydrogels is that it can take several hours for the hydrogel to become fully hydrated and to expand to sufficient size to cause it to be retained in the stomach. Since non-expanding dosage forms remain in the stomach on average for about 1 to 3 hours, there is a high probability that known expanding dosage forms like that of the '153 patent will pass through the pylorus before attaining a sufficient size to obstruct passage. The rate-limiting factor in the expansion of ordinary hydrogels is the rate of diffusion of water to non-surfacial hydrogel material in the dosage form. Conventional hydrogels are not very porous when they are dry, so transport of water into the hydrogel can be slow. In addition, a low permeability gelatinous layer forms on the surface of wetted hydrogel, which further slows transport of water into the hydrogel.
One approach to solving the problem of slow expansion has been the development of superporous hydrogels. Superporous hydrogels have networks of pores of 100μ diameter or more. At that diameter, the pores are able to rapidly transport water deep into the superporous hydrogel by capillary action. Water reaches the non-surfacial hydrogel material quickly resulting in a rapid expansion of the superporous hydrogel to its full extent. Superporous hydrogels are still under development and have not been approved for pharmaceutical use by the U.S. Food and Drug Administration. There are also shortcomings attendant to the use of superporous hydrogels. They tend to be structurally weak and some are unable to withstand the mechanical stresses of the natural contractions that propel food out of the stomach and into the intestine. The superporous hydrogels tend to break up quickly into particles too small to be retained.
Chen, J. and Park, K. Journal of Controlled Release 2000, 65, 73-82, describes a superporous hydrogel whose mechanical strength is improved by the polymerization of precursor hydrogel monomers in the presence of several superdisintegrants. The result of the polymerization described by Chen and Park is a new substance having interconnecting cross-linking networks of polyacrylate and, e.g., cross-linked carboxymethyl cellulose sodium. Such interconnecting networks are not expected to have the same physical properties as conventional hydrogels made from the same precursor hydrogel monomers.
Another general strategy for retaining dosage forms in the stomach is intragastric floatation, as exemplified in U.S. Pat. Nos. 4,140,755 and 4,167,558. Intragastric floatation systems are less dense than gastric fluid and avoid passage through the pylorus by floating on top of the gastric fluid. These systems generally take one of three forms. Hydrodynamically balanced floating systems comprise capsules of the active ingredient and a hydrogel that forms a gelatinous coating upon contact with water that slows further uptake of water. In one example of such a system, a capsule containing the non-hydrated hydrogel and an active ingredient dissolves upon contact with gastric fluid. The hydrogel then comes into contact with gastric fluid and forms a gelatinous coating on the surface. The gelatinous coating traps air inside the hydrogel thereby making the mass buoyant. Expansion of the hydrogel also makes it less dense and therefore more buoyant. Another form of intragastric floatation system is a gas generating system, which evolves gas upon contact with water. Gas bubbles trapped in the dosage form make it buoyant. Another variation on the intragastric floatation systems are low density core systems, wherein the active ingredient is coated over a low density material like puffed rice.
The floating dosage forms and expanding dosage forms previously described operate by different gastric retention mechanisms, each with its own requirements to be effective. A floatation system must remain buoyant even while absorbing gastric fluid. An expanding system must be capable of expansion to a size sufficient to obstruct transit into the intestine and yet be small enough in its non-hydrated state to be swallowed. The present invention includes embodiments that expand as well as embodiments that expand and generate gas.
There is a particular need for an effective gastric retention system for treatment of Parkinson's disease with levodopa. Parkinson's disease is a degenerative condition associated with reduced dopamine concentrations in the basal ganglia region of the brain. The deficiency is considered to be caused by oxidative degradation of dopaminergic neurons in the substantia nigra. The preferred course of therapy is to restore dopamine concentration in the brain by administration of levodopa, a metabolic precursor of dopamine that, unlike dopamine, is able to cross the blood-brain barrier. The metabolic transformation of levodopa to dopamine is catalyzed by the aromatic L-amino acid decarboxylase enzyme. This enzyme is found throughout the body including gastric juices and the mucosa of the intestine. Treatment with levodopa alone requires administration of large doses of the drug due to extracerebrial metabolism by this enzyme. The resulting high concentration of extracerebrial dopamine causes nausea in some patients. To overcome this problem, levodopa is usually administered with an inhibitor of the aromatic L-amino decarboxylase enzyme such as carbidopa.
Levodopa eases the symptoms of Parkinsonism by temporarily boosting dopamine concentration in the central nervous system, but it is not a cure. During prolonged treatment of the disease with levodopa, the body typically becomes less sensitive to levodopa concentration in the brain. The body requires more frequent dosing to suppress the manifestations of the disease: tremor, muscular rigidity, lack of facial expression, and altered gait. As the blood plasma concentration drops, the return of disease manifestations in the so-called “off state,” signals the need for immediate administration of another dose. There is, unfortunately, a delay between ingestion of levodopa and a return to the “on state” suppression of the disease symptoms. Aggressive administration of levodopa to circumvent off state symptoms of rigidity and akinesia, can lead to equally disabling involuntary motions called dyskinesias.
From the foregoing, it will be appreciated that it is highly desirable to be able to administer levodopa as a sustained release oral dosage form capable of stabilizing the serum level of levodopa in a patient. Levodopa/carbidopa is currently available in Sinamet® CR controlled release tablets (DuPont Pharma) that slowly erode to release the actives. According to the Physician's Desk Reference, 54th ed., the tablets use a polymeric based drug delivery system. Prolonged suppression of disease manifestations with these tablets is limited by the mechanism of absorption of levodopa from the gastrointestinal tract. Levodopa is absorbed by the active transport mechanism for amino acids, which is most active in the duodenum region of the small intestine. Sustained release is therefore limited by the transit time of the dosage form through the stomach and duodenum which, though highly variable from individual-to-individual and dependent upon nutritional state, typically takes only about 3 to 4 hours. Levodopa released after the 3-4 hour therapeutic window has passed is not bioavailable. Sinemet® CR controlled release tablets have about 75% of the bioavailability of Sinemet® conventional release tablets. Physicians Desk Reference, 54th edition (Medical Economics Co., publisher, 2000) at p. 979.
Another problem in Parkinson's disease therapy that could be addressed with an improved controlled release levodopa delivery vehicle is the reduction in plasma levodopa concentration that occurs while a patient is sleeping. Parkinson's patients usually awaken in the morning in the off state and must wait for a morning dose of levodopa to take effect before they can function comfortably. It would be highly desirable if a Parkinson's disease patient could take levodopa in the evening, while under the therapeutic effect of a previous dose, and wake up in the morning without the manifestations of the disease. For such purpose, the drug delivery vehicle ideally would not only extend the release of levodopa over time, but would also delay release of levodopa until the early morning hours before the patient awakens so that the patient would awaken when the therapeutic effect of the dose is near its maximum.
Therefore, there is a need for a controlled release levodopa oral dosage form that is able to deliver levodopa to a patient's bloodstream over a longer time period than is currently possible without resort to a regimen of frequent dosing, and the fluctuations in plasma levodopa levels that occur with frequent dosing. Further, there is a need for improvement in controlled-release forms that improves the bioavailability of levodopa as well as lowers the dosage frequency.
There is also a particular need for an effective gastric retention system for use in treatment of children with hyperactivity and attention deficit disorder. Methylphenidate, the mainstay in treatment of hyperactivity, has a short half-life in the human body and, so, frequent dosing (about every four hours) is required. Children therefore need to take the drug when they are in school. This poses administrative problems for schools that are asked to see that a child takes his medication. Sustained release formulations of methylphenidate have been developed. Methylphenidate is currently available in Ritalin®-SR sustained-release tablets (Novartis). According the Physician's Desk Reference, 54th ed., Ritalin®-SR tablets contain cellulose compounds and povidone. Another sustained release formulation of methylphenidate is proposed in U.S. Pat. No. 5,874,090. Unfortunately, patients become tolerant to a sustained high blood level of methylphenidate and require more medication to suppress their hyperactivity or distractibility.
U.S. Pat. No. 6,034,101 (and WO 98/14168) discloses a methylphenidate dosage form that is designed to overcome the development of tolerance within a single dosage interval. This dosage form delivers methylphenidate in pulses of ascending intensity. However, the dosage form is not a gastric retention form. Therefore, while the first pulse of drug is released in the stomach, subsequent pulses are delivered in the jejunum, ileum, and/or colon. Methylphenidate is more readily absorbed by the stomach than by the intestine. Consequently, the pulses that are designed to be the most intense are the least bioavailable because they are released downstream of the stomach. Another dosage form for delivering methylphenidate in pulses is described in U.S. Pat. No. 5,837,284. In addition to the mismatch between the ascending dose profile and the descending bioavailability as the dosage form passes through the GI tract, these pulsed methods have the drawback that the higher dosages can increase the severity and occurrence of the side effects experienced with the drug, especially sleep disturbance.
Allowing a sufficiently long drug-free interval between doses of methylphenidate is a more preferred approach to avoid acute tolerance than using an ascending drug profile. However, the pulse delivery systems used to deliver methylphenidate over greater periods of time suffer the same bioavailability problems as the pulsed dosage forms with ascending profiles. Thus, there is a need for a gastric retention pulsed delivery system that can deliver methylphenidate in pulses with consistent bioavailability.
There is clearly a need for improvement in gastric retention-controlled release technology and a particular need for improved gastric retention dosage forms of levodopa and methylphenidate.